Control of HIV drug resistance in older patients

老年患者艾滋病毒耐药性的控制

• 批准号: 7897760
• 负责人: Alonso Heredia
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897760
• 关键词: Affect; Affinity; Aging; Anti-Retroviral Agents; Antibodies; Binding; Biological Assay; CCR5 gene; Cell Line; Cell fusion; Cells; Chemokine (C-C Motif) Receptor 5; Clinical Trials; Comorbidity; Cytochrome P450 3A4; Development; Dose; Drug Delivery Systems; Drug Interactions; Drug resistance; Educational workshop; Elderly; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV drug resistance; Heart; Highly Active Antiretroviral Therapy; In Vitro; Individual; Infection; Inosine Monophosphate; Integrase; Kidney; Length; Licensing; Life; Life Cycle Stages; Life Expectancy; Ligands; Liver diseases; Metabolism; Mutate; Mycophenolic Acid; National Institute of Allergy and Infectious Disease; Nature; Nucleosides; Oxidoreductase; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Predisposition; Protease Inhibitor; Proteins; Quality of life; RANTES; RNA Interference; RNA-Directed DNA Polymerase; Resistance; Resistance development; Resveratrol; Reverse Transcriptase Inhibitors; Ribonucleotide Reductase; Sirolimus; Testing; Therapeutic; Time; Toxic effect; Variant; Viral; Viral Drug Resistance; Viral Proteins; Virion; Virus; age related; alternative treatment; analog; cellular targeting; density; drug sensitivity; env Gene Products; experience; improved; in vivo; inhibitor/antagonist; neuropsychiatry; non-nucleoside reverse transcriptase inhibitors; nucleoside analog; older patient; prevent; public health relevance; resistance mechanism; small molecule; stoichiometry; treatment strategy; viral resistance; virus envelope

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has dramatically increased life expectancy in HIV infection and by 2015 more than half of HIV patients in the U.S. will be older than 50. Elderly HIV patients often experience comorbidities such as neuropsychiatric complications and heart, kidney and liver disease, which require additional medications. For those patients failing HAART due to HIV drug resistance, the recently developed antiretroviral class of CCR5 antagonists represents an alternative treatment option. Maraviroc is currently approved for patients infected with drug-resistant HIV viruses that use CCR5 as a coreceptor (the so-called R5 strains) and Vicriviroc is in Phase III clinical trials. Importantly, CCR5 antagonists, unlike HIV non-nucleoside reverse transcriptase and protease inhibitors, neither induce nor inhibit cytochrome P450 3A4, which is responsible for the metabolism of many medications commonly used by the elderly. Thus, CCR5 antagonists may provide safer treatment options for elderly patients with drug-resistant R5 HIV infection because of the reduced potential for drug interaction with coadministered medications. However, recent clinical trials demonstrate that R5 HIV can develop resistance to CCR5 antagonists. Viruses resistant to CCR5 antagonists often gain the ability to use antagonist-bound CCR5, which is manifested by incomplete viral inhibition (plateau at <100%) in drug susceptibility assays. In Preliminary Results we demonstrate that these inhibition plateaus are affected by CCR5 density, with increased viral suppression achieved at lower CCR5 densities. These results provide the first indication that decreasing CCR5 can control viral resistance to CCR5 antagonists. Our long-term goal is to control HIV drug-resistance by targeting cellular components required in the HIV life cycle. The objective of this proposal is to determine the mechanism by which R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density. Our hypothesis is that R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density because the affinity of the resistant virus envelope protein is lower for antagonist-bound CCR5 than for free CCR5. We have one Specific Aim: To determine the affinity of CCR5 antagonist-resistant gp120 for free and bound-CCR5, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) and the stoichiometry (number of antagonist-bound CCR5 molecules engaged per virion) in CCR5 antagonist-resistant R5 HIV infection. We will determine the affinity of resistant gp120 for free and bound-CCR5 by binding assays, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) in pseudovirus infections and cell-cell fusion assays, and the stoichiometry in pseudovirus infection of cell lines with varying CCR5 densities. Successful proof of this hypothesis will suggest CCR5 internalization (i.e., using RANTES analogs) and inhibition of expression (i.e., using RNA interference) as potential therapeutic strategies to restore sensitivity to CCR5 antagonists and thus improve quality of live for HIV patients, especially for the elderly. PUBLIC HEALTH RELEVANCE: According to the 2007 Workshop on HIV Infection and Aging, organized among others by the NIAID and the NIA, "identification of particular antiretroviral drugs or treatment strategies that may be more effective in older HIV-infected individuals is essential". For elderly HIV patients failing HIV treatment due to viral drug resistance, the newly developed CCR5 antagonists represent an attractive treatment option because they are active against drug-resistant HIV and because they have reduced potential for toxicity. Since HIV can develop resistance to CCR5 antagonists, we will identify the mechanism of drug resistance and potential strategies for its control, which will improve quality of life for patients with drug resistant HIV, especially for the elderly.

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）大大增加了HIV感染者的预期寿命，到2015年，美国一半以上的HIV患者将超过50岁。老年艾滋病毒感染者往往患有神经精神并发症和心脏、肾脏和肝脏疾病等合并症，需要额外的药物治疗。对于那些由于HIV耐药性而导致HAART失败的患者，最近开发的抗逆转录病毒类CCR 5拮抗剂代表了一种替代治疗选择。马拉韦罗目前已被批准用于感染耐药HIV病毒的患者，这些病毒使用CCR 5作为辅助受体（所谓的R5株），而Vicriviroc正在进行III期临床试验。重要的是，与HIV非核苷逆转录酶和蛋白酶抑制剂不同，CCR 5拮抗剂既不诱导也不抑制细胞色素P450 3A 4，细胞色素P450 3A 4负责老年人常用的许多药物的代谢。因此，CCR 5拮抗剂可以为耐药R5 HIV感染的老年患者提供更安全的治疗选择，因为与联合用药的药物相互作用的可能性降低。然而，最近的临床试验表明，R5 HIV可以对CCR 5拮抗剂产生耐药性。对CCR 5拮抗剂具有抗性的病毒通常获得使用拮抗剂结合的CCR 5的能力，这通过药物敏感性测定中的不完全病毒抑制（平台<100%）来证明。在初步结果中，我们证明了这些抑制平台受CCR 5密度的影响，在较低的CCR 5密度下实现了增加的病毒抑制。这些结果首次表明降低CCR 5可以控制病毒对CCR 5拮抗剂的耐药性。我们的长期目标是通过针对艾滋病毒生命周期所需的细胞成分来控制艾滋病毒的耐药性。本提案的目的是确定对CCR 5拮抗剂耐药的R5 HIV在降低的CCR 5密度下恢复敏感性的机制。我们的假设是，对CCR 5拮抗剂具有抗性的R5 HIV在降低的CCR 5密度下恢复敏感性，因为抗性病毒包膜蛋白对拮抗剂结合的CCR 5的亲和力低于对游离CCR 5的亲和力。我们有一个明确的目标：为了确定CCR 5拮抗剂抗性gp 120对游离和结合的CCR 5的亲和力，在CCR 5拮抗剂抗性R5 HIV感染中，CD 4和CCR 5（游离和拮抗剂结合的）结合的滞后期的长度和化学计量（每个病毒体接合的拮抗剂结合的CCR 5分子的数目）。我们将通过结合试验确定抗性gp 120对游离和结合的CCR 5的亲和力，在假病毒感染和细胞-细胞融合试验中确定CD 4和CCR 5（游离和拮抗剂结合的）结合的滞后期的长度，以及在具有不同CCR 5密度的细胞系的假病毒感染中的化学计量。这一假设的成功证明将表明CCR 5内化（即，使用RANTES类似物）和表达的抑制（即，使用RNA干扰）作为潜在的治疗策略，以恢复对CCR 5拮抗剂的敏感性，从而改善HIV患者，特别是老年人的生活质量。公共卫生关系：根据2007年由NIAID和NIA等组织的艾滋病毒感染和老龄化问题讲习班，“确定对老年艾滋病毒感染者可能更有效的特定抗逆转录病毒药物或治疗战略至关重要”。对于由于病毒耐药性而未能接受HIV治疗的老年HIV患者，新开发的CCR 5拮抗剂代表了一种有吸引力的治疗选择，因为它们对耐药性HIV具有活性，并且因为它们具有降低的毒性潜力。由于HIV可以对CCR 5拮抗剂产生耐药性，因此我们将确定耐药性的机制及其控制的潜在策略，这将改善耐药HIV患者的生活质量，特别是老年人。

项目成果

Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc.

• DOI: 10.4137/cmt.s2365
• 发表时间: 2009
• 期刊: Clinical medicine. Therapeutics
• 作者: Latinovic O;Kuruppu J;Davis C;Le N;Heredia A
• 通讯作者: Heredia A

CCR5 Inhibitors and HIV-1 Infection.

CCR5 抑制剂和 HIV-1 感染。

• DOI: 10.33696/aids.1.001
• 发表时间: 2019
• 期刊: Journal of AIDS and HIV treatment
• 作者: Latinovic,OlgaS;Reitz,Marvin;Heredia,Alonso
• 通讯作者: Heredia,Alonso

CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells.

CCR5 抗体 HGS004 和 HGS101 优先抑制药物结合的 CCR5 感染并恢复原代细胞中马拉维罗耐药 HIV-1 的药物敏感性。

• DOI: 10.1016/j.virol.2010.12.029
• 发表时间: 2011
• 期刊: Virology
• 影响因子: 3.7
• 作者: Latinovic,Olga;Reitz,Marvin;Le,NhutM;Foulke,JamesS;Fatkenheuer,Gerd;Lehmann,Clara;Redfield,RobertR;Heredia,Alonso
• 通讯作者: Heredia,Alonso